Project Summary Title: Personalized target selection for TMS therapy using functional vs. structural connectivity MRI Transcranial magnetic stimulation (TMS) is an FDA-approved treatment for major depressive disorder (MDD). Remission rates are estimated to be around 30%, similar to other antidepressant therapies yet still suboptimal. A key reason for the variability in response is the lack of an individualized approach that identifies the cortical therapeutic target for each patient. A proposed strategy is to use functional connectivity MRI to identify the topography of functional networks relevant to MDD. In this project, we propose a novel strategy to personalized identification of TMS targets by using diffusion MRI (dMRI) to identify the white matter bundles that connect two critical nodes affected by MDD: the left prefrontal cortex (PFC) and the subgenual cingulate (SGC). We will study 500 subjects from the Human Connectome Project (HCP) and 20 patients with MDD who were treated with TMS. We will use state-of-the-art functional connectivity and diffusion MRI data and analyses. Our goal is to quantify and compare, for the first time, the reliability of these methods to identify cortical targets for TMS therapy. In addition we will study the clinical efficacy of dMRI-guided TMS by retrospectively analyzing the relationship between therapeutic response and location of the stimulated TMS target in relation to the optimal dMRI node. Last, we will use sophisticated dMRI metrics to assess the changes in white matter microstructure induced by TMS and how they relate to clinical efficacy (therefore defining anatomical mechanisms of action and therapeutic targets). Results from this project will support future prospective trials aiming to confirm target engagement and therapeutic response using individualized dMRI-guided TMS in MDD and other neuropsychiatric conditions.